Autoimmune disease affects over 25 million Americans, and has an economic impact of over 100 billion dollars per year. These disorders result from a breakdown of the intrinsic regulatory pathways that limit T cell activation and differentiation, and from a failure of regulatory T cells (Treg) to extrinsically suppress conventional T cell (Tconv) proliferation and effector function. Genetic studies in both humans and mice strongly implicate the cytokine IL-2 in the risk of developing Grave's disease, rheumatoid arthritis, celiac disease, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and type 1 diabetes (T1D). The majority of the disease-associated single nucleotide polymorphisms (SNP) are located in the ~100 kb or intergenic space between the IL2 and IL21 genes, and the molecular basis for the genetic link between IL2 and autoimmunity is not understood. We have new evidence that distal, intergenic cis-regulatory elements contribute to the regulation of IL2. We find that CD28 costimulation induces looping between a distal element and the il2 promoter, and this distal element can greatly enhance IL2 transcription in promoter-reporter assays. The research proposed in this application will explore and establish the long-range regulatory architecture of the IL2 locus, paving the way for an important new understanding of the genetic basis for autoimmune disease.